Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)

  • J Med Chem. 2018 Dec 27;61(24):11021-11036. doi: 10.1021/acs.jmedchem.8b01291.
Atwood K Cheung  1 ,  Brian Hurley  1 ,  Ryan Kerrigan  1 ,  Lei Shu  1 ,  Donovan N Chin  1 ,  Yiping Shen  1 ,  Gary O'Brien  1 ,  Moo Je Sung  1 ,  Ying Hou  1 ,  Jake Axford  1 ,  Emma Cody  1 ,  Robert Sun  1 ,  Aleem Fazal  1 ,  Cary Fridrich  1 ,  Carina C Sanchez  1 ,  Ronald C Tomlinson  1 ,  Monish Jain  1 ,  Lin Deng  1 ,  Keith Hoffmaster  1 ,  Cheng Song  1 ,  Mailin Van Hoosear  1 ,  Youngah Shin  1 ,  Rebecca Servais  1 ,  Christopher Towler  2 ,  Marc Hild  1 ,  Daniel Curtis  1 ,  William F Dietrich  1 ,  Lawrence G Hamann  1 ,  Karin Briner  1 ,  Karen S Chen  3 ,  Dione Kobayashi  3 ,  Rajeev Sivasankaran  1 ,  Natalie A Dales  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States.
  • 2. Novartis Pharmaceuticals , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States.
  • 3. SMA Foundation , 888 Seventh Avenue, Suite 400 , New York , New York 10019 , United States.
PMID: 30407821 DOI: 10.1021/acs.jmedchem.8b01291
Abstract

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

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